Cocaine blocks neuronal dopamine (DA) uptake, prolongs the presence of DA in the synapse and thus acts indirectly as a DA receptor agonist. The positive reinforcing effects of cocaine have been hypothesized to involve these actions upon mesolimbic and mesocortical dopaminergic systems. The phenomenon of cocaine-induced behavioral sensitization, which is induced by repetitive cocaine administration, is associated with mesolimbic and nigrostriatal dopaminergic systems. These observations have aroused considerable interest in understanding changes in DA sensitivity produced by cocaine in these pathways. The hypothesis to be tested is that dopaminergic systems become sensitized with single or repeated administration of cocaine because the properties of the presynaptic DA transporter protein are altered leading to uncoupling of the neuronal uptake pump from its recognition binding site and/or enhanced transport of DA out of the terminal via a reversal of the pump. Temporal changes in 3H-DA uptake, its recognition binding site (3H-mazindol binding) and amphetamine-induced release of endogenous DA in the nigrostriatal, mesolimbic and mesocortical systems will be compared to changes in locomotor activity and stereotypic behavior induced by single and repeated cocaine administration. Properties of DA receptors will also be measured to determine whether or not they are regulated in a manner to compensate for the changes in the presynaptic release/uptake mechanism. Presynaptic DA receptor function will be assessed by measuring the D-2 receptor modulation of electrically-evoked release of endogenous DA from slices. The properties of 3H-mazindol binding sites and D-2 and D-1 DA receptors will be determined using digital subtraction autoradiography in tissue sections containing either cell bodies or terminals of these three dopaminergic systems. Pharmacological controls for these experiments will investigate whether administration of drugs that block catecholamine uptake, act as direct DA agonists or are local anesthetics lead to similar behavioral sensitization and neurochemical changes. This set of experiments will test the specificity of the observations made following cocaine administration. Recently, desipramine and bromocriptine have been reported to be successful in the treatment of cocaine abuse in humans. Whether current or subsequent administration of these agents, together with cocaine, reverses any of the cocaine-induced changes in behavioral sensitization and/or DA neurochemistry will be determined. These experiments should help to resolve whether alterations in the presynaptic DA transporter are responsible for the behavioral sensitization produced by cocaine and whether these neurochemical changes can be reversed by pharmacological treatment.